The present invention is directed to oxazolidinones; oxazolidinone compositions; oxazolidinone combinational libraries; and methods for their preparation and use.
Oxazolidinones are compounds where an amine group and a hydroxyl group on adjacent carbon atoms have been cyclized to form a 5-membered ring containing a carbonyl group. Certain oxazolidinones have been shown to exhibit a variety of biological activities. For example, some oxazolidinones are inhibitors of monoamine oxidase-B, an enzyme implicated in Parkinson""s disease. See, for example, Ding et al., J Med. Chem. 36:3606-3610 (1993).
A a ten step synthesis of oxazolidinone antibiotics has been described. U.S. Pat. No. 5,547,950. A four step synthesis of the antibacterial compound U-100592 also has been reported. Schauss et al., Tetrahedron Letters, 37:7937-7940 (1996). A five step preparation of enantiomerically pure cis- and trans-N-(propionyl)hexahydrobenzoxazolidin-2-ones further was reported. De Parrodi et al., Tetrahedron: Asymmetry, 8:1075-1082 (1997).
Scientists have reported that certain oxazolidinone derivatives exhibit beneficial antibacterial effects. For instance, N-[3-[3-fluoro-4-(morpholin-4-yl)phenyl]2-oxooxazolidin-5(s)-ylmethyl] acetamide (below) has been reported to be useful for the treatment of bacterial infections. Lizondo et al., Drugs of the Future, 21:1116-1123 (1996). 
The synthesis of the oxazolidinone antibacterial agent shown below has been reported. Wang et al, Tetrahedron, 45:1323-1326 (1989). This oxazolidinone was made using a process that included the reaction of an aniline with glycidol to provide an amino alcohol, and the diethylcarbonate mediated cyclization of the amino alcohol to afford an oxazolidinone. 
The synthesis of oxazolidinone antibacterial agents, including the compound shown below has been reported. U.S. Pat. No. 4,705,799. The process used to make the compound shown below included a metal mediated reduction of a sulfonyl chloride to provide a sulfide. 
The synthesis of oxazolidinone antibacterial agents, including the pyridyl compound shown below has been reported. U.S. Pat. No. 4,948,801. The process used included an organometallic mediated coupling of an organotin compound and an aryl iodide. 
Synthetic routes to oxazolidinones often allow a chemist to produce only one compound at a time. These laborious methods can provide a limited number of compounds for evaluation in a biological screen. These methods cannot, however, provide the number of compounds required to supply a high-throughput biological screen, an assay technique whereby the activity of thousands of drug candidates, for example, per week, may be analyzed. This limitation on compound production is of practical importance since high-throughput screens are desirable and efficient for the discovery of new drugs.
Provided are oxazolidinones and combinatorial libraries, compositions comprising oxazolidinones, as well as methods of their synthesis and use. Using the methods provided herein, one of skill in the art can rapidly produce the large number of compounds required for high-throughput screening.
In one embodiment, provided are methods for the solid phase synthesis of oxazolidinones.
In one embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide functionality, opening the epoxide with an amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an allylic amine to a solid support, oxidizing the olefin of the allylic amine to provide an epoxide, opening the epoxide with an amine, and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching allylamine to a solid support, oxidizing the olefin of allylamine to provide an epoxide, opening the epoxide with an amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide, opening the epoxide with an amino acid and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide, opening the epoxide with an aromatic amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
Methods also are provided for the synthesis of oxazolidinone combinatorial libraries.
In one embodiment, the method comprises attaching an olefin group to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units, and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an allylic amine to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units and. cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching allyl amine to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amino acid units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with aromatic amine units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
Provided are a variety of oxazolidinones and combinatorial libraries thereof. In one embodiment, the oxazolidinones have the structure: 
where R1 is selected from the group consisting of alkyl, heteroalkyl aryl and heteroaryl; R2 is selected from the group consisting of hydrogen, alkyl, heteroalkyl; aryl and heteroaryl; R3 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl; R11 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl; and R12 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, oxazolidinones and combinatorial libraries are provided wherein the oxazolidinones are of the structure 1b, wherein R2, R3, R4 and R5 are, independently, hydrogen, alkyl, 
heteroalkyl, heteroaryl or an electron withdrawing group; R6 is acyl or sulfonyl; and, R1 is one of the following functional groups: C(O)NR7R8, wherein R7 and R8 are, independently, hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(O)OR9, wherein R9 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(O)R10, wherein R10 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; SR11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; S(O)2R11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; S(O)R11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; NR12R13, wherein R12 and R13 are, independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl or heteroaryl; 2-oxazolyl, wherein R14 is at the 4-position and R15 is at the 5-position of the oxazolyl, and wherein R14 and R15 are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group; 2-aminothiazolyl, wherein R16 is at the 4-position and R17 is at the 5-position of the thiazole, and wherein R16 and R17, are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group; and, CH2NR18R19, wherein R18 and R19 are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl.
All compounds disclosed herein can exist as different isomer forms including stereoisomers and enantiomerically pure forms, and all such isomers and forms are within the scope of the invention. For example, while structure 1b is shown with the preferred embodiment of a S isomer at the 5 position of the oxazolidinone, the R isomer is within the scope of the invention. Similarly, in all of the other oxazolidinone compounds, in the case where a preferred stereoisomer is shown at the 5 position of the oxazolidinone, both stereoisomers are within the scope of the invention.
In one embodiment of structure 1b, R1 is C(O)R7R8.
In another embodiment of structure 1b, R1 is C(O)OR9.
In another embodiment of structure 1b, R1 is C(O)R10.
In another embodiment of structure 1b, R1 is SR11.
In another embodiment of structure 1b, R1 is S(O)2R11.
In another embodiment of structure 1b, R1 is S(O)R11.
In another embodiment of structure 1b, R1 is NR12R13. In another embodiment, R1 is NRx(Cxe2x95x90O)Ry, wherein Rx and Ry are independently hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl;
or R1 is NRx(SO2)Ry, wherein Rx and Ry are independently hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl with the proviso that Ry is not H;
In another embodiment of structure 1b, R1 is 2-oxazolyl, wherein R14 is at the 4-position and R15 is at the 5-position of the oxazole group.
In another embodiment of structure 1b, R1 is 2-amninothiazolyl, wherein R16 is at the 4-position and R17 is at the 5-position of the aminothiazolyl group.
In another embodiment of structure 1b, R1 is CH2NR18R19.
In another embodiment of structure 1b, R1 is C(O)NR7R8; and, R3, R4 and R5 are hydrogen.
In another embodiment of structure 1b, R1 is C(O)NR7R8; R3, R4 and R5 are hydrogen; and, R2 is fluorine.
In another embodiment of structure 1b, R1 is C(O)NR7R8; R3, R4 and R5 are hydrogen; R2 is fluorine; and, R6 is C(O)CH3.
In another embodiment of structure 1b, R1 is C(O)NR7R8; R3, R4 and R5 are hydrogen; R2 is fluorine; R6 is C(O)CH3; and, R7 is hydrogen.
In another embodiment of structure 1b, R1 is C(O)NR7R8; R3, R4 and R5 are hydrogen; R2 is fluorine; R6 is C(O)CH3; R7 is hydrogen; and, R8 is heteroaryl.
A variety of methods of preparing combinatorial libraries comprising oxazolidinones are provided.
In one embodiment, the method is for the preparation of oxazolidinones, such as those of structure 1b. The method comprises the steps of: attaching a plurality of aryl oxazolidinones to a plurality of solid supports; functionalizing the 4-position of the aryl groups of the attached oxazolidinones; and, optionally, removing the oxazolidinones from the solid supports.
In another embodiment, the aryl oxazolidinone is attached to a solid support through the reaction of an iminophosphorane with a carbonyl containing resin to form an imine. In another embodiment, the aryl oxazolidinone is attached to a solid support through the reaction of an amine with a carbonyl containing resin to form an imine.
In another embodiment, the aryl oxazolidinone is attached to a solid support through the reaction of an iminophosphorane with a carbonyl containing resin to form an imine, and the imine is reduced to form an amine. In another embodiment, the aryl oxazolidinone is attached to a solid support through the reaction of an amine with a carbonyl containing resin to form an imine, and the imine is reduced to form an amine.
Also provided are biologically active oxazolidinones and compositions comprising biologically active oxazolidinones. For example, the oxazolidinones may have antibiotic activity.
In one embodiment, the biologically active oxazolidinones are of the structure 1b.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is C(O)NR7R8.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15 at the 5-position of the oxazole.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position and R17 at the 5-position of the aminothiazolyl.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is C(O)NR7R8, and wherein R3, R4 and R5 are hydrogen.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15 at the 5-position of the oxazole, and wherein R3, R4 and R5 are hydrogen.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position and R17 at the 5-position of the aminothiazole, and wherein R3, R4 and R5 are hydrogen.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is C(O)NR7R8, and wherein R3, R4 and R5 are hydrogen, and further wherein R2 is fluorine.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15 at the 5-position of the oxazole, and wherein R3, R4 and R5 are hydrogen, and further wherein R2 is fluorine.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position and R17 at the 5-position of the aminothiazole, and wherein R3, R4 and R5 are hydrogen, and further wherein R2 is fluorine.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is C(O)NR7R8, wherein R7 is hydrogen and R8 is 5-chloropyridine-3-yl, thiazole-2-yl, 5xe2x80x2-(5-aminopyridine-2-yl)thiopyridine-3xe2x80x2-yl, or pyridine-3-yl; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is fluorine; and further wherein R6 is C(O)CH3.
In another embodiment, the biologically active oxazolidinones are of the structure 1b, wherein R1 of the oxazolidinone is C(O)NR7R8, wherein R7 is hydrogen and R8 is 5-chloropyridine-3-yl; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is fluorine; and further wherein R6 is C(O)CH2SMe.
In another embodiment, the biologically active oxazolidinones are of the structure 1b wherein R1 of the oxazolidinone is C(O)NR7R8, wherein R7 is hydrogen and R8 is 5-chloropyridine-3-yl; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is fluorine; and further wherein R6 is C(O)CHCH(pyridine-3-yl).
In another embodiment, the biologically active oxazolidinones are of the structure 1b wherein R1 of the oxazolidione is 5-amino-4-cyanooxazole-2-yl; and wherein R2 is fluorine; and further wherein R3, R4 and R5 are hydrogen; and still further wherein R6 is C(O)CH3.
In another embodiment, the biologically active oxazolidinones are of the structure 1b wherein R1 of the oxazolidione is 4-phenylthiazole-2-yl-amino; and wherein R2 is fluorine; and further wherein R3, R4 and R5 are hydrogen; and still further wherein R6 is C(O)CH3.
A variety of methods of synthesizing biologically active oxazolidinones are provided.
In one embodiment, methods are provided for the preparation of oxazolidinones, such as those of the structure 1b, and comprise the steps of: providing an iminophosphorane; mixing the iminophosphorane with a resin that comprises carbonyl groups to form an imine intermediate; and, reducing the imine intermediate to afford a compound attached to the resin through an amine linkage. In another embodiment, the iminophosphorane is provided from an azide that is reacted with a phosphine. In another embodiment, the iminophosphorane is provided from an amine that is reacted with a (trisubstituted)phosphine dihalide.
In another embodiment, the resin comprising carbonyl groups is of the structure 
wherein R23 is hydrogen, alkyl, aryl, O-alkyl or O-aryl; R24 is hydrogen, CH3O or NO2; R25 is (CH2)nCONH, wherein n is an integer ranging between 1 and about 5; and, the filled circle is a polymeric support.
In another embodiment of structure 1c, R23 is hydrogen, R24 is CH3O, R25 is (CH2)3CONH and the filled circle is Tentagel, (cross-linked)polystyrene, (cross-linked)polyethylene glycol or polyethyleneglycol-polystyrene compositions.
Methods also are provided of synthesizing biologically active oxazolidinone compositions from a corresponding amine. In one embodiment, the method is for the preparation of oxazolidinones, for example, of the structure 1b, and comprises the steps of: reacting an amine with a resin that comprises carbonyl groups to form an imine intermediate; and, reducing the imine intermediate to afford a compound attached to the resin through an amine linkage.